Project 3 Prevention and Treatment of Graft-versus-host Disease: The goal of this project is to improve survival after allogeneic hematopoietic cell transplantation (HCT) by more effective prevention and treatment of acute graft-versus-host disease (GVHD). Aim 1 is directed toward prevention of GVHD through prophylactic oral administration of a topically active glucocorticoid that has little systemic effect. Separate phase II clinical trials will be carried out among patients who have myeloablative and non-myeloablative conditioning regimens before HCT. These studies will test the hypothesis that prophylactic administration of beclomethasone diproprionate can greatly decrease the incidence of GVHD involving the gastro-intestinal tract and possibly other target organs as well. Aim 2 is directed toward decreasing the amount of steroid treatment needed to control GVHD among patients who develop this complication after HCT. Patients who develop acute GVHD after HCT with a myeloablative conditioning regimen will be treated with low-dose alemtuzumab to test the hypothesis that depletion of T cells after administration of the antibody will accelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, without increasing the risk of opportunistic infections. Patients who develop GVHD after HCT with a non- myeloablative conditioning regimen will be treated with low-dose methotrexate to test the hypothesis that the effects of this drug on donor T cells will accelerate resolution of the disease and permit more rapid withdrawal of steroid treatment, without increasing the risk of recurrent malignancy. In Aim 3, phase I and phase II clinical trials will be carried out to test the hypothesis that administration of a CD28-specific antibody is effective for treatment or prevention of acute GVHD, as suggested by previous laboratory studies. Patients with GVHD that cannot be controlled by currently available treatments will be enrolled in a phase I clinical trial. If results of the phase I study are encouraging, then a phase II study will be carried out to test whether administration of the antibody can prevent GVHD in humans. Relevance to Public Health: The studies in this project could lead to the development of more effective methods for preventing or treating harmful immune reactions that can occur when blood or marrow transplantation is used to treat leukemia, lymphoma, myeloma and other related disorders. Successful development of such methods would improve the safety and applicability of blood or marrow transplantation for treatment of these diseases. '